DESCRIPTION: (Applicant's Abstract) My career goals for the next five years of this proposal are directed toward the aim of increasing my progress toward the understanding the biochemical mechanisms underlying tolerance and dependence on cannabinoids and opioids. I would like the contributions of my laboratory to be recognized as important to public health. Specific goals are as follows: 1) to continue to my professional growth by the maintenance of a progressive research group which incorporates the best technical approaches to address our hypotheses to further the scientific development of the laboratory; 2) to continue to increase my collaborations with scientists from all areas of drug abuse research, from behavioral through molecular areas, in order to incorporate a variety of ideas, methods, and hypotheses into my research; 3) to mentor many young scientists and to continue my drug education activities; and 4) to increase participation in scientific societies, to organize symposia for national meetings, become an officer in a society, and in general make a greater contribution to the drug abuse research field. The KO2 would allow for the fulfillment of these goals by freeing my schedule of non-research oriented activities to allow me to maximally develop my research laboratory, and to generate ideas and preliminary data for future grants, to guide and mentor students and postdoctoral fellows, and to continue to develop my skills, particularly in terms of gene regulation and other aspects of molecular biology. My Research Plan employs a systematic study of cannabinoid and opioid antinociception, tolerance and dependence through two intertwined projects using in vivo and in vitro techniques including evaluation of the production of and phosphorylation of proteins, immunohistochemical localization of receptors, and the regulation of the mRNA for such proteins. The "Plan" is based upon our considerable preliminary data indicating an interaction of acutely administered cannabinoids with the kappa opioids, and is designed to compare and contrast the cute versus the chronic effects of cannabinoids and/or opioids on three interrelated parameters: 1) alterations in the release of endogenous opioids; 2) alterations in opioid receptor number and /or affinity or phosphorylation state; and 3) alterations in the number or affinity of cannabinoid receptors, calcium and potassium channel subunit composition and phosphorylation in both brain and spinal cord.